Molecular mechanisms conferring risk for colorectal cancer

Colorectal cancer (CRC, or Bowel cancer) is the fourth most common cancer in UK, accounting for over 16 000 deaths annually (Cancer Research UK, 2016 statistics). It is also perhaps best understood of all cancer forms, in terms of how it forms, and which genes have a role in its formation. However, despite the large amount of work that has concentrated on understanding CRC, we still do not know all the genetic mutations that cause it.

Furthermore, although more than 60 inherited genetic variants that increase risk for CRC are known, the mechanisms that generate the inherited disease risk are not well understood. This is in large part because the genetic variants that carry the largest fraction of population-level risk reside in the region of the genome that does not code for proteins. The variants are presumed to affect the amount of

proteins made in particular cells, by affecting DNA binding of proteins called transcription factors. However, actual evidence for this mechanism is largely lacking, mostly because we do not understand exactly how the part of the genome where the variants are functions, and how changes in DNA sequence affect binding of the transcription factors and activity of genes.

The proposed research project aims to understand how mutations or variations in DNA sequences that bind the transcription factors changes the activity of genes, and how the changed activity leads to tumour formation. This is basic research utilizing novel high throughput methods and computational data analysis of the experimental results. The project will first generate vast amounts of data in a laboratory, and then utilize and understand it using tailor-made computer programs.

The work is very much a collaboration between biological and computational scientists, who will work closely together to understand basic mechanisms of how cells can tell when and where the genes written in their DNA should be active. The researchers will seek to understand 'the second genetic code'. The first genetic code that describes how DNA sequence is converted to protein sequence was decoded already more than 50-years ago, and the first draft of human genome, which describes the sequence of the chemical letters A, C, G and T found in all human cells was published in 2001.

Determining the human genome sequence has had a very large impact in several fields of biology and medicine. However, knowing just the order of the letters is not enough to understand how they instruct cells to grow, and how this process goes wrong in cancer. Our project aims to understand how the network of proteins and genes talk and regulate each other when reading the second genetic code.

To solve these issues is a short-term benefit to scientific community in terms of deeper understanding, novel methods and computational tools aiding to understand how cancer develops. In the longer term, our results are expected to lead to many applications that help to predict, prevent and treat disease. For example, the results and tools developed within the project can be used to improve predicting of who is at risk to develop cancer.

In a wider context, the proposed project in part of a broader effort to use advanced genomic and computational tools to understand the basis of disease. Genetic variants that are located between genes, and are so common that most people have many of them have recently been found to be important in increasing risk to most common diseases. We therefore expect that the methods and tools developed within the project will be widely applicable to the study of the mechanisms that cause other common diseases.

Hence, this project will not only impact research on colorectal cancer but will have broader implications for research, prevention and treatment of other common diseases.